This invention relates to radiation synovectomy for arthritic joints and, more particularly, to novel biodegradable and biologically compatible glass microspheres or beads and their use in carrying out radiation synovectomy of arthritic joints.
Current medical management of rheumatoid arthritis includes patient education, appropriate rest and physical therapy, and the use of anti-inflammatory drugs for relief of pain and inflammation. Ruddy, S., The Management of Rheumatoid Arthritis. Textbook of Rheumatology, 2nd ed., W. B. Saunders Co. Philadelphia, 1985, p. 979. Patients who do not respond to these modalities may require therapy with anti-malarial agents such as hydroxychloroquine (Bell, C. L., Hydroxychloroquine Sulfate in Rheumatoid Arthritis: Long-Term Response Rate and Predictive Parameters, American Journal of Medicine, 75:46, 1983) or remission inducing agents including gold salts (Empire Rheumatism Council, Gold Therapy in Rheumatoid Arthritis: Final Report of a Multicentre Controlled Trial, Ann. Rheum. Dis. 20:315, 1961), penicillamine (Multicentre Trial Group: Controlled Trial of d(-) Penicillamine in Severe Rheumatoid Arthritis, Lancet, 1:275, 1973), or azathioprine (Abel, T. et al., Long-Term Effects of Azathioprine in Rheumatoid Arthritis, Arthritis Rheum. 21:539, 1978). Despite the efficacy of these drugs, patient response is variable and improvement may not occur until treatment has extended for three to six months. When a few joints remain swollen and painful and interfere with the patient's progress, intra-articular instillation of corticosteroids may be used as an adjunct to systemic therapy. This local remedy, however, may be ineffective or may last only a few days (Owen, D. S., Aspiration and Injection of Joints and Soft Tissues, Textbook of Rheumatology, supra, p. 546).
Surgery may be used in several different ways to help the patient with rheumatoid arthritis. Surgery can help relieve pain, it can prevent further deformity and loss of function, or at least allay these problems, and when destruction has occurred, reconstructive procedures can return function to a part or a limb. Sledge, C. B., Introduction to the Surgical Management of Arthritis, Textbook of Rheumatology, supra, p. 1787.
Most of the operations done on rheumatoid patients relieve pain. Fusions of joints, total joint replacement and synovectomy are examples of procedures that significantly reduce pain. Conaty (Conaty, J. P., Surgery of the Hip and Knee in Patients with Rheumatoid Arthritis, Journal of Bone and Joint Surgery, 55(A):301, 1973) states that in rheumatoid arthritis, synovectomy was the most successful procedure for preserving motion of a joint, except for total joint arthroplasty. This procedure, then, is preventive. Even so, eventually the synovium regenerates and the process continues (Patzakis, M. J. et al., A Visual, Histological, and Enzymatic Study of Regenerating Rheumatoid Synovium in the Synovectomized Knee, Journal of Bone and Joint Surgery, 55(A):287, 1973). Total joint surgery will relieve any or all of the aforementioned disabilities, but brings with it other problems that must be taken into consideration by the surgeon. Some of these are: (1) cost, (2) the risk of infection, (3) the fact that the implants may come loose and be painful, and (4) the fact that the implant may break with unusual use.
Chemical and radioisotope synovectomy (synoviorthesis) constitutes an effective alternative to operative therapy. The advantages of synoviorthesis are: (1) simple techniques employed in their use, (2) decreased or no hospitalization, (3) lower costs, (4) early and easier mobilization of the patient, and (5) a surgical synovectomy remains an alternative treatment should the synoviorthesis not work.
In general, the results of radioisotope synoviorthesis appear to be superior to those attained with chemical synovectomy. (Menkes, C. J., et al. La Synoviorthese a L'acide Osmique Chez L'hemophilie, Rev. Rhum. 40:255, 1973; Oka, M., et al., The Fate and Distribution of Intra-Articularly Injected Osmium Tetraoxide, Acta Rheum. Scand., 16:271, 1970; Delbarre, F., et al., La Synoviorthese par les Radio-Isotopes a la Main et au Poignet, Rev. Rhum., 40:205, 1973). Some chemical agents that have been used are thio-tepa (Flatt, A. E., Intra-Articular Thio-Tepa in Rheumatoid Disease of the Hands, Rheumatism, 18:70, 1962; Fearnley, M. D., Intra-Articular Thio-Tepa Therapy in Rheumatoid Arthritis, Ann. Phys. Med., 7:294, 1963; Zuckner, J., et al., Evaluation of Intra-Articular Thio-Tepa in Rheumatoid Arthritis, Ann. Rheum. Dis., 25:178, 1966; Gross, D., Chemische Synovektomie mit Senfgas bei Primar Chronischer Polyarthritis, Z. Rheumforsch, 22:456, 1963; Mondragon Kalb, M., Thiotepa en al Tratamiento de la Arthritis Rhumatoide, Medicina, 15:82, 1965), osmic acid (Menkes, C. J., et al., La Synoviorthese a L'acide Osmique Chez L'hemophilie, Rev. Rhum., 40:255, 1973; Oka, M., et al., The Fate and Distribution of Intra-Articularly Injected Osmium Tetraoxide, Acta Rheum. Scand., 16:271, 1970; Von Reis, G., et al., Intra-Articular Injections of Osmic Acid in Painful Joint Affections, Acta Med. Scand. Suppl., 259: 27, 1951; Berglof, F. E., Further Studies on the Use of Osmic Acid in the Treatment of Arthritis, Acta Rheum. Scand., 10:92, 1964; Martio, J., et al., Intra-Articular Osmic Acid in Juvenile Rheumatoid Arthritis, Scand. J. Rheumatol, 1:5, 1972; Brattstrom, H., et al., Kombinierte Chemische und Operative Synovektomie es Kniegelenks, Orthapade, 2:73, 1973; Jakubowski, S., et al., Indikatronen zur Synovektomie bei pcP, orthopade, 2:6, 1973), varicoid (Tillman, K., Chemische Synovektomie, Orthopade, 2:10, 1973) and gold (Delbarre, F., et al., supra). Radioactive substances include Gold-198, Yttrium-90 citrate, Yttrium-90 resin, Rhenium-186, Erbium-169, Yttrium-90 ferric hydroxide, Radium-224 and Phosphorus-32 chromic phosphate (Sledge, C. B., supra).
Beta-emitting radionuclides are considered the most useful for radiotherapeutic applications because of the moderate linear energy transfer (LET) of the ionizing particle (electron) and its intermediate range (typically several millimeters in tissue). In contrast, gamma rays deliver dosage at lower levels over much greater distances, thus hampering the localization of the dose and diluting its effect. Alpha particles represent the other extreme; they deliver very high LET dosage, but have an extremely limited range and must, therefore, be in intimate contact with the cells of the tissue to be treated. In addition, alpha emitters are generally heavy metals, which limits the possible chemistry and presents undue hazards from leakage of radionuclide from the area to be treated.
It is fortuitous that beta emitters, the most useful radiotherapeutic radionuclides, are also the ones most copiously produced by neutron capture in nuclear reactors, the most powerful sources of radioisotopes. Reactor-produced isotopes number in the thousands, giving researchers a wide choice of isotopes of various half-lives, beta energies, gamma emissions, and chemical properties. Gamma emissions, while not as useful for therapy as beta emissions, play an important role in that they permit the distribution of radioisotope in the body to be observed using an Anger gamma ray camera or single photon computed tomography (SPECT) instrument. This permits direct observation and, to some extent, quantification of radionuclide leakage from an organ or a joint and also provides positive verification of the potency of joint injection and distribution of the radionuclide in the research animal.
Treatment of the different depths of diseased synovium in joints of disparate size, such as the finger joints and the knee, requires isotopes of different average beta range. It is important to achieve a "kill" of sufficient depth to be efficacious without causing significant necrosis of overlying normal tissues.
The effectiveness of a radioisotope depends upon the fact that it gives off beta radiation which kills tissue along with the fact that it gives off no alpha and little gamma radiation. The latter type of radiation penetrates too far, affecting tissues adversely, whereas beta radiation has a short penetration distance, varying in millimeters for each radioisotope. Radioisotopes also have different half-lives, some being far too long or too short for any practical use. These factors, then, have to be considered in the application of a radioisotope for synoviorthesis.
Sledge et al. (Treatment of Rheumatoid Synovitis of the Knee with Intra-Articular Injection of Dysprosium-165 Ferric Hydroxide Macroaggregates, Arthritis and Rheumatism, 29(2):153, 1986) have used macroaggregates of ferric hydroxide (FHMA) combined with dysprosium-165. This compound does present the problem of some leakage to local lymph nodes and other tissues. Also, dyprosium-165 has a half-life of 2.3 hours, making it necessary for the patient to be close to a nuclear reactor, severely limiting the use of this radioisotope. Even with these drawbacks, the clinical results were noteworthy, as 80% of patients treated for chronic synovitis of the knee with dysprosium-165-FHMA were improved at one year, and nearly 90% of patients with Stage 1 roentgenographic changes had excellent, good, or fair results (Sledge, et al., Intra-Articular Radiation Synovectomy, Clinical Orthopaedics and Related Research, 182:37, 1984). These results and the results of others (Boerbooms, A. M., et al., Radio-Synovectomy in Chronic Synovitis of the Knee Joint in Patients with Rheumatoid Arthritis, European Journal of Nuclear Medicine, 10:446, 1985; Multicentre Trial Group: Intra-Articular Radioactive Yttrium and Triamcinolone Hexacetonide: An Inconclusive Trial, Ann. Rheum. Dis., 43:620, 1984; Kyle, V., et al., Yttrium-90 Therapy and .sup.99m Tc Pertechnetate Knee Uptake Measurements in the Management of Rheumatoid Arthritis, Annals of the Rheumatic Diseases, 42:132, 1983; Rosenthall, L., Use of Radiocolloids for Intra-Articular Therapy for Synovitis, In Therapy in Nuclear Medicine, Grune and Stratton, Inc., New York, 1978, p. 147; Spooren, P. et al., Synovectomy of the Knee with 90-Y, European Journal of Nuclear Medicine, 10:441, 1985) show that radiation synoviorthesis has a role in the treatment of inflammatory synovitis.
In our copending, coassigned application for U.S. patent Ser. No. 673,123, filed Nov. 19, 1984, now U.S. Pat. No. 4,789,501, dated Dec. 6, 1988, we disclose novel microspheres for use in the radiation therapy of liver cancer and other cancerous or tumor bearing tissue. Such microspheres have not, however, been used or suggested for use in radiation synovectomy of arthritic joints and may not be suitable for use in radiation synovectomy by reason of the radionuclides incorporated therein having relatively long physical half-lives.
There is a continuing need, therefore, for improved microspheres and methods for radiation synovectomy of arthritic joints.